Lung Cancer in Never-Smokers

Abstract

Although smoking is the main cause of lung cancer, lung cancer among never-smokers is not uncommon and is the 7th leading cause of cancer deaths worldwide. This thesis examines three potential etiologic pathways in never-smoker lung cancer ? chronic inflammation resulting in uncontrolled cell proliferation, direct damage arising from exposure to carcinogens, and pro-carcinogenic estrogen pathway signaling in lung tissue. The factors that we investigated included chronic airway inflammation and genetic polymorphisms in the inflammatory pathway (examining 6 polymorphisms in 5 genes), previous Non-Steroidal Anti-Inflammatory Drug (NSAID) use, exposure to domestic inhalants, dietary factors, and reproductive factors and polymorphisms in the estrogen signaling pathways (examining 5 polymorphisms in 4 genes). Data obtained by trained interviewers using a standardized questionnaire, and where permitted, blood and saliva samples, of Chinese female incident lung cancer patients, and controls frequency-matched by age and date of admission in two hospital-based case-control studies (conducted 1996-1998 and 2005-2008) were used. In total, 702 cases and 1578 controls were recruited, of whom 433 cases (61.7%) and 1375 controls (87.1%) were never-smokers. Tuberculosis was positively associated with lung cancer, although this was not statistically significant. There was no effect of asthma, atopy or chronic productive cough individually, but the presence of one or more of these conditions was positively associated with lung cancer in individuals possessing specific genotypes in the IL1-?-31T/C and IL1RN genes. The IL6-634 G allele was positively associated with lung cancer. Regular use of aspirin was inversely associated with lung cancer, and this inverse association was strongest for those starting use 1 to 5 years prior to admission, and those whose duration of use was 12 to 60 months. These data together suggest that inflammatory processes are important in never-smoker lung carcinogenesis. A positive relationship with daily exposure to incense or mosquito coils and to cooking fumes was observed only among smokers, with no relationship seen among never-smokers. These interactions were statistically significant. Our data suggest that smokers are more susceptible to the risk-enhancing effects of other inhalants. We postulate that these results may in part be explained by the chronic airway inflammation induced by chronic smoking. Meat and, in particular, fish consumption was inversely associated with lung cancer in never-smokers, but null effects were seen for processed meats and dietary heterocyclic amines. The inverse association of fish consumption with lung cancer could be due to omega-3 fatty acids (a prominent nutrient found in fish) and their effects, among others, in reducing inflammation in the local tissue milieu. Parity and menstrual cycle length were inversely associated with lung cancer, while age at first birth, age at menopause and reproductive period were positively associated. The COMT rs4680 A allele was positively associated with lung cancer, but null effects were seen with other polymorphisms. These data suggest that high circulating estrogen levels over the lifetime are associated with lung cancer risk, especially in never-smokers, and that this effect could be at least partially mediated through direct catechol estrogen damage to genetic material. Collectively, the studies in this thesis implicate both the inflammatory and estrogen pathways in lung carcinogenesis. Perhaps the most significant aspect of this set of findings is that chronic inflammation may play a bigger role in never-smoker lung cancer than has been previously recognized. Further research is needed to confirm these findings and to delineate the precise role played by inflammation and reproductive factors in never-smoker lung carcinogenesis.